The growth and survival of neoplastic cells is regulated both by internal genetic control within tumor cells and by host factors. In a very small population of cancer patients, progression of malignant tumors can be partially or completely reversed by an unknown host mechanism termed "spontaneous regression". Lack of animal models for spontaneous regression has hampered the efforts to identify the factors involved in this mechanism of tumor resistance. Dr. Cui and his colleagues have identified a unique, genetically-determined mouse trait conferring the spontaneous regression of late-stage ascites induced by the transplantation of aggressive mouse sarcoma 180 cells. The spontaneous regression of late-stage ascites is complete and permanent in the mice carrying the mutation. This trait also protects the mice against tumor development following transplantation of mouse leukemia cells. Immunological studies revealed that tumor cells elicited a migration of immune cells to the tumor site. The infiltrating immune cells form cell-cell aggregates and induced necrotic rupture of tumor cells, eliminating tumor cells in a few hours after tumor transplantation. Genetic studies suggest that this unique response of activated immune cells to tumor cells may be caused by a dominant mutation in these mice. Initial genotype analysis established a linkage of this mutation to two adjacent microsatellite markers on mouse chromosome 4. In this proposal Dr. Cui has assembled a group of experts from genomics, pathology, immunology, carcinogenesis and biochemistry to determine the genetic basis, cellular mechanism and anti-tumor spectrum of this powerful tumor resistance trait. The long-term objective of this proposal is to determine if a similar mechanism can be also effective in human cancer treatment and prevention. This proposal has 3 specific aims: 1) to identify the immunological components for tumor rejection; 2) to determine the anti-tumor spectrum of tumor rejection, 3) to identify the gene(s) affected by the mutation. Completion of these aims will provide a comprehensive understanding of the biological mechanism of this unique, powerful resistance to tumors. Necessary tools will be developed to extend these studies to search for similar genes in humans and to design better, more efficient strategies of cancer treatment and prevention.